Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.

• MeSH
• afibrinogenemie * epidemiologie   genetika   komplikace   MeSH
• fibrinogen genetika   MeSH
• hemostatika * MeSH
• krvácení genetika   MeSH
• lidé MeSH
• prospektivní studie MeSH
• retrospektivní studie MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fibrinogen MeSH
• hemostatika * MeSH

Here, we present the first case of fibrinogen variant FGG c.8G>A. We investigated the behaviour of this mutated fibrinogen in blood coagulation using fibrin polymerization, fibrinolysis, fibrinopeptides release measurement, mass spectrometry (MS), and scanning electron microscopy (SEM). The case was identified by routine coagulation testing of a 34-year-old man diagnosed with thrombosis. Initial genetic analysis revealed a heterozygous mutation in exon 1 of the FGG gene encoding gamma chain signal peptide. Fibrin polymerization by thrombin and reptilase showed the normal formation of the fibrin clot. However, maximal absorbance within polymerization was lower and fibrinolysis had a longer degradation phase than healthy control. SEM revealed a significant difference in clot structure of the patient, and interestingly, MS detected several posttranslational oxidations of fibrinogen. The data suggest that the mutation FGG c.8G>A with the combination of the effect of posttranslational modifications causes a novel case of hypofibrinogenemia associated with thrombosis.

• MeSH
• afibrinogenemie * komplikace   genetika   MeSH
• dospělí MeSH
• fibrin metabolismus   MeSH
• fibrinogen genetika   metabolismus   MeSH
• fibrinogeny abnormální * genetika   metabolismus   MeSH
• hemostatika * MeSH
• lidé MeSH
• oxidační stres MeSH
• posttranslační úpravy proteinů MeSH
• trombóza * komplikace   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• fibrin MeSH
• fibrinogen MeSH
• fibrinogeny abnormální * MeSH
• hemostatika * MeSH

Congenital fibrinogen disorders are caused by mutations in genes coding for fibrinogen and may lead to various clinical phenotypes. Here, we present a functional and structural analysis of 4 novel variants located in the FGB gene coding for fibrinogen Bβ chain-heterozygous missense BβY416C and BβA68S, homozygous nonsense BβY345*, and heterozygous nonsense BβW403* mutations. The cases were identified by coagulation screening tests and further investigated by various methods. Fibrin polymerization had abnormal development with decreased maximal absorbance in all patients. Plasmin-induced fibrin degradation revealed different lytic phases of BβY416C and BβW403* than those of the control. Fibrinopeptide cleavage measured by reverse phase high pressure liquid chromatography of BβA68S showed impaired release of fibrinopeptide B. Morphological properties, studied through scanning electron microscopy, differed significantly in the fiber thickness of BβY416C, BβA68S, and BβW403*, and in the fiber density of BβY416C and BβW403*. Finally, homology modeling of BβA68S showed that mutation caused negligible alternations in the protein structure. In conclusion, all mutations altered the correct fibrinogen function or structure that led to congenital fibrinogen disorders.

• Klíčová slova
• FGB, afibrinogenemia, congenital fibrinogen disorder, dysfibrinogenemia, functional assays, homology modeling, hypofibrinogenemia, scanning electron microscopy,
• MeSH
• afibrinogenemie krev   diagnóza   genetika   MeSH
• fenotyp * MeSH
• fibrinogen chemie   genetika   metabolismus   MeSH
• genetická predispozice k nemoci * MeSH
• genetické asociační studie MeSH
• hemokoagulace MeSH
• konformace proteinů MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• molekulární modely MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• novorozenec MeSH
• senioři MeSH
• vyšetření krevní srážlivosti MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• FGB protein, human MeSH Prohlížeč
• fibrinogen MeSH

INTRODUCTION: Congenital dysfibrinogenemia and hypofibrinogenemia are rare diseases characterized by inherited abnormality in the fibrinogen molecule, resulting in functional defects (dysfibrinogenemia) or low fibrinogen plasma levels (hypofibrinogenemia). MATERIALS AND METHODS: We have described two abnormal fibrinogens - fibrinogen Hranice (γ Phe204Val) and Praha IV (γ Ser313Gly). The carrier of the Hranice mutation was a 40-year-old female with low fibrinogen levels. The carrier of the Praha IV mutation was a 42-year-old man with a history of idiopathic thrombosis, low functional fibrinogen levels, and a prolonged thrombin time. RESULTS: Fibrin polymerization kinetics measurement was normal in both cases (after the addition of either thrombin or reptilase), as well as was fibrinolysis. Scanning electron microscopy and confocal microscopy revealed significantly wider fibers in both cases, when compared with fibers prepared from healthy control samples. Although both cases are situated in the γ-nodule, they manifested differently. While the γ Ser313Gly mutation manifested as dysfibrinogenemia with a thrombotic background, the γ Phe204Val mutation manifested as hypofibrinogenemia without clinical symptoms. The mutation sites of both fibrinogens are in highly conserved regions of the fibrinogen γ chains. γ Ser313 is situated in a class 16:18 β hairpin and is involved in hydrogen bonding with γ Asp320. γ Phe204 is situated in an inverse γ turn and may be involved in π-π interactions. CONCLUSIONS: Both mutations cause conformational changes in fibrinogen, which lead either to impaired fibrinogen assembly (fibrinogen Hranice) or abnormal fibrinogen function (fibrinogen Praha IV).

• Klíčová slova
• Abnormal fibrinogens, Coagulation, Fibrinogen, Hereditary coagulation disorders, Thrombosis,
• MeSH
• afibrinogenemie krev   vrozené   genetika   metabolismus   MeSH
• bodová mutace * MeSH
• dospělí MeSH
• fibrin genetika   metabolismus   ultrastruktura   MeSH
• fibrinogen genetika   metabolismus   ultrastruktura   MeSH
• fibrinogeny abnormální genetika   metabolismus   ultrastruktura   MeSH
• fibrinolýza MeSH
• lidé MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fibrin MeSH
• fibrinogen MeSH
• fibrinogeny abnormální MeSH
• fibrinopeptides gamma MeSH Prohlížeč

• MeSH
• afibrinogenemie krev   genetika   MeSH
• fibrinogen genetika   metabolismus   MeSH
• fibrinogeny abnormální genetika   metabolismus   MeSH
• homozygot MeSH
• lidé MeSH
• předškolní dítě MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• dopisy MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fibrinogen Aalpha MeSH Prohlížeč
• fibrinogen MeSH
• fibrinogeny abnormální MeSH

Fibrinogen—a 340-kDa glycoprotein—plays a crucial role in blood coagulation, platelet aggregation, wound healing, and other physiological processes. A mutation in fibrinogen may lead to congenital dysfibrinogenemia,a rare disease characterized by the functional deficiency of fibrinogen. About 580 cases of abnormal fibrinogens have been reported worldwide; thereof 335 cases in the fibrinogen Aa chain[1]. To our knowledge, only five cases of abnormal fibrinogens with two mutations [2–6] and one case of two different mutations in the same family [7] have been described earlier. A 52-year-old female was examined for bleeding. Routine hemostasis screening resulted in a diagnosis of dysfibrinogenemia. Functional testing revealed prolonged fibrin polymerization, prolonged lysis of the clot, abnormal fibrin morphology,and fibrinopeptides release. Genetic analysis showed two heterozygous nonsense mutations—previously described mutation AaGly13Glu and a novel mutation Aa Ser314Cys. The mutation Aa Gly13-Glu was found in her brother and niece, but there was no evidence in either of the mutation Aa Ser314Cys. While mutation Aa Gly13Glu is responsible for abnormal fibrinopeptide release and prolonged thrombin time, the novel mutation Aa Ser314Cys seems to affect fibrin morphology and fibrinolysis.

• MeSH
• afibrinogenemie krev   komplikace   genetika   MeSH
• bodová mutace * MeSH
• dítě MeSH
• dospělí MeSH
• elektroforéza sérových bílkovin MeSH
• fibrin ultrastruktura   MeSH
• fibrinogeny abnormální genetika   izolace a purifikace   MeSH
• fibrinopeptid A metabolismus   MeSH
• hemoragické poruchy etiologie   MeSH
• heterozygot MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikroskopie elektronová rastrovací MeSH
• nesmyslný kodon * MeSH
• posttranslační úpravy proteinů MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• fibrin MeSH
• Fibrinogen Sumperk II MeSH Prohlížeč
• fibrinogeny abnormální MeSH
• fibrinopeptid A MeSH
• nesmyslný kodon * MeSH

Hereditary dysfibrinogenemia is a rare disorder wherein an inherited abnormality in fibrinogen structure may result in defective fibrin function and/or structure. Congenital hypofibrinogenemia is a rare autosomal bleeding disorder, either recessive or dominant, characterized by a low fibrinogen plasma level. A 28-year-old asymptomatic woman (fibrinogen Rokycany) and a 54-year-old man with thrombosis and pulmonary embolism (fibrinogen Znojmo) were investigated for a suspected fibrinogen mutation after abnormal coagulation tests results were obtained. DNA sequencing showed the heterozygous point mutation Bβ Asn351Lys in fibrinogen Rokycany and the heterozygous point mutation Bβ Arg237Ser in fibrinogen Znojmo, respectively. The kinetics of fibrinopeptide release was found to be normal in both cases. Fibrinolysis was impaired in the Znojmo variant. The average fibril diameters of Znojmo fibrin was slightly increased, but not differing significantly from normal; formed by less fibrils with abrupt fibril terminations. Rheological studies revealed a softer clot. Rokycany fibrin was formed by significantly narrower fibrils than normal fibrin; and the clot was denser than the control clot. Rheological studies revealed a stiffer clot. Impaired fibrinolysis and abnormal clot morphology may be the cause of thrombotic episodes in the patient with Znojmo mutation. New cases of hypofibrinogenemia and dysfibrinogenemia, found by routine coagulation testing, were genetically identified as a novel fibrinogen variants Bβ Asn351Lys (fibrinogen Rokycany) and Bβ Arg237Ser (fibrinogen Znojmo), respectively.

• MeSH
• afibrinogenemie genetika   MeSH
• bodová mutace * MeSH
• dospělí MeSH
• fibrinogen genetika   MeSH
• fibrinogeny abnormální genetika   MeSH
• heterozygot MeSH
• lidé středního věku MeSH
• lidé MeSH
• reologie krve MeSH
• trombóza etiologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BBeta fibrinogen MeSH Prohlížeč
• fibrinogen Rokycany MeSH Prohlížeč
• fibrinogen Znojmo MeSH Prohlížeč
• fibrinogen MeSH
• fibrinogeny abnormální MeSH

A 2-year-old asymptomatic boy and his relatives were investigated for a suspected fibrinogen mutation after coagulation tests revealed a decreased functional fibrinogen level (family A). Eight-year-old and 1-year-old asymptomatic brothers were investigated for a suspected fibrinogen mutation after coagulation tests revealed a decreased functional fibrinogen level and prolonged thrombin time (family B). To identify whether genetic mutations were responsible for these dysfibrinogens, DNA extracted from the blood was analyzed. Fibrin polymerization and fibrinolysis were measured by a turbidimetric method at 450 nm. DNA analysis was performed by the Sanger method. Mass spectroscopy was performed on a Biflex IV mass spectrometer. DNA sequencing showed the heterozygous point mutation Aα Arg16His in the fibrinogen of family A and the heterozygous point mutation Aα Arg16Cys in the fibrinogen of family B. Kinetics of fibrinopeptide release, fibrinolysis, and fibrin polymerization were impaired in the carriers of the mutations in both families. Mass spectroscopy showed the presence of mutant fibrinogen chains in circulation. Scanning electron microscopy revealed thicker fibrin fibers, differing significantly from the normal control in both cases. Two cases of asymptomatic dysfibrinogenemias, found by routine coagulation testing, were genetically identified as new cases of fibrinogen variants Aα Arg16His and Aα Arg16Cys.

• MeSH
• afibrinogenemie vrozené   diagnóza   genetika   MeSH
• bodová mutace * MeSH
• dítě MeSH
• fibrin metabolismus   MeSH
• fibrinogen genetika   MeSH
• heterozygot MeSH
• kojenec MeSH
• lidé MeSH
• mutační analýza DNA metody   MeSH
• sourozenci MeSH
• trombinový čas MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fibrin MeSH
• fibrinogen MeSH

Abnormal coagulation properties indicative of a dysfibrinogen were found in the plasma of a 72-year-old male with multiple myeloma (IgGkappa, stage IIIA). The patient had high paraprotein concentration (85.75 g/l) and prolonged thrombin time (76.8 s), activated partial thromboplastin time (39.5 s), prothrombin time (23.5 s) and reptilase time (72.0 s). The fibrinogen level was increased. The fibrin polymerization induced by both thrombin and reptilase was impaired. Scanning electron microscopy revealed abnormal clot morphology. After six months of treatment, the paraprotein level decreased (19.48 g/l) and coagulation normalized as well as fibrin polymerization and fibrin clot morphology. It was found that the paraprotein interacts with the gamma-chain of fibrinogen. Acquired dysfibrinogenemia associated with multiple myeloma was diagnosed in the 72-year-old patient.

• MeSH
• afibrinogenemie etiologie   terapie   MeSH
• fibrin chemie   MeSH
• fibrinogen metabolismus   MeSH
• lidé MeSH
• mikroskopie elektronová rastrovací MeSH
• mnohočetný myelom komplikace   MeSH
• paraproteiny analýza   metabolismus   MeSH
• peptidové fragmenty metabolismus   MeSH
• senioři MeSH
• vyšetření krevní srážlivosti MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fibrin MeSH
• fibrinogen gamma (151-411) MeSH Prohlížeč
• fibrinogen MeSH
• paraproteiny MeSH
• peptidové fragmenty MeSH

OBJECTIVE: A 22-yr-old woman had abnormal preoperative coagulation test results and congenital dysfibrinogenaemia was suspected. PATIENTS AND METHODS: The patient from Liberec (Czech Republic) had a low fibrinogen plasma level as determined by Clauss method, normal fibrinogen level as determined by immunoturbidimetrical method, and prolonged thrombin time. To identify the genetic mutation responsible for this dysfibrinogen, genomic DNA extracted from the blood was analysed. Fibrin polymerisation measurement, kinetics of fibrinopeptide release, fibrinogen clottability measurement and scanning electron microscopy were performed. RESULTS: DNA sequencing showed the heterozygous fibrinogen gamma Y262C mutation. Kinetics of fibrinopeptide release was normal, however fibrin polymerisation was impaired. Fibrinogen clottability measurement showed that only about 45% molecules of fibrinogen are involved in the clot formation. Scanning electron microscopy revealed thicker fibres, which were significantly different from the normal control. CONCLUSION: A case of dysfibrinogenaemia, found by routine coagulation testing, was genetically identified as a novel fibrinogen variant (gamma Y262C) that has been named Liberec.

• MeSH
• afibrinogenemie genetika   MeSH
• dospělí MeSH
• fibrinogeny abnormální genetika   MeSH
• hemokoagulace genetika   MeSH
• lidé MeSH
• missense mutace * MeSH
• mutační analýza DNA MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• fibrinogeny abnormální MeSH